Abraham Thomas, Armold Michael, McGovern Christopher, Harms John F, Darok Matthew C, Gigliotti Christopher, Adair Bernadette, Gray Jennifer L, Kelly Deborah F, Adair James H, Matters Gail L
Department of Neural and Behavioral Sciences, Penn State College of Medicine, P.O. Box 850, Hershey, PA 17036, USA.
Department of Biochemistry and Molecular Biology, Penn State College of Medicine, P.O. Box 850, Hershey, PA 17036, USA.
Biomedicines. 2024 May 7;12(5):1024. doi: 10.3390/biomedicines12051024.
The poor prognosis for pancreatic ductal adenocarcinoma (PDAC) patients is due in part to the highly fibrotic nature of the tumors that impedes delivery of therapeutics, including nanoparticles (NPs). Our prior studies demonstrated that proglumide, a cholecystokinin receptor (CCKR) antagonist, reduced fibrosis pervading PanIN lesions in mice. Here, we further detail how the reduced fibrosis elicited by proglumide achieves the normalization of the desmoplastic tumor microenvironment (TME) and improves nanoparticle uptake. One week following the orthotopic injection of PDAC cells, mice were randomized to normal or proglumide-treated water for 3-6 weeks. Tumors were analyzed ex vivo for fibrosis, vascularity, stellate cell activation, vascular patency, and nanoparticle distribution. The histological staining and three-dimensional imaging of tumors each indicated a reduction in stromal collagen in proglumide-treated mice. Proglumide treatment increased tumor vascularity and decreased the activation of cancer-associated fibroblasts (CAFs). Additionally, PANC-1 cells with the shRNA-mediated knockdown of the CCK2 receptor showed an even greater reduction in collagen, indicating the CCK2 receptors on tumor cells contribute to the desmoplastic TME. Proglumide-mediated reduction in fibrosis also led to functional changes in the TME as evidenced by the enhanced intra-tumoral distribution of small (<12 nm) Rhodamine-loaded nanoparticles. The documented in vivo, tumor cell-intrinsic anti-fibrotic effects of CCK2R blockade in both an immunocompetent syngeneic murine PDAC model as well as a human PDAC xenograft model demonstrates that CCK2R antagonists, such as proglumide, can improve the delivery of nano-encapsulated therapeutics or imaging agents to pancreatic tumors.
胰腺导管腺癌（PDAC）患者预后较差，部分原因在于肿瘤具有高度纤维化的特性，这阻碍了包括纳米颗粒（NPs）在内的治疗药物的递送。我们之前的研究表明，胆囊收缩素受体（CCKR）拮抗剂丙谷胺可减少小鼠胰腺上皮内瘤变（PanIN）病变中的纤维化。在此，我们进一步详细阐述丙谷胺引发的纤维化减少如何实现促结缔组织增生性肿瘤微环境（TME）的正常化并改善纳米颗粒摄取。在原位注射PDAC细胞一周后，将小鼠随机分为饮用正常水或丙谷胺处理水的组，持续3至6周。对肿瘤进行离体分析，检测纤维化、血管生成、星状细胞活化、血管通畅性和纳米颗粒分布情况。肿瘤的组织学染色和三维成像均显示，丙谷胺处理的小鼠间质胶原减少。丙谷胺治疗增加了肿瘤血管生成，并降低了癌症相关成纤维细胞（CAF）的活化。此外，通过短发夹RNA（shRNA）介导敲低CCK2受体的PANC - 1细胞显示出胶原蛋白的减少更为明显，表明肿瘤细胞上的CCK2受体促成了促结缔组织增生性TME。丙谷胺介导的纤维化减少还导致TME发生功能变化，这可通过小尺寸（<12 nm）负载罗丹明的纳米颗粒在肿瘤内分布增强得到证明。在免疫健全的同基因小鼠PDAC模型以及人PDAC异种移植模型中记录的CCK2R阻断在体内、肿瘤细胞内在的抗纤维化作用表明，丙谷胺等CCK2R拮抗剂可改善纳米包封治疗药物或成像剂向胰腺肿瘤的递送。
